Sinomenine derivative metabolite as well as preparation method, pharmaceutical composition and application thereof

A technology of metabolites and derivatives, applied in the field of biomedicine, can solve problems such as unsatisfactory treatment effects, adverse reactions of patients, and high prices, and achieve the effects of novel structure, recovery of bone marrow hematopoietic function, and low toxicity

Pending Publication Date: 2021-10-12
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the overall suppression of the immune system by immunosuppressants will bring serious adverse reactions

Method used

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  • Sinomenine derivative metabolite as well as preparation method, pharmaceutical composition and application thereof
  • Sinomenine derivative metabolite as well as preparation method, pharmaceutical composition and application thereof
  • Sinomenine derivative metabolite as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Biosynthesis of sino-wcj-43-M1

[0048] Step 1: using esterase to catalyze the hydrolysis of sino-wcj-43 to sino-wcj-43-M1. The reaction system is PBS buffer (pH=7.4), pig liver esterase 25U / mL, sino-wcj-43 0.5mg / mL, reacted in 37°C water bath for 2h, and the conversion rate of hydrolysis reaction can reach 90% by HPLC-UV detection above.

[0049] Step 2: Add an equal volume of acetonitrile to the reaction solution to precipitate protein, centrifuge at 5500rpm for 10min to remove the protein precipitate, evaporate the supernatant to remove the organic solvent under reduced pressure, extract 5 times with ethyl acetate, evaporate to dryness under reduced pressure, dissolve a small amount of mobile phase, and use the preparation solution Phase separation and purification of sino-wcj-43-M1. The preparative column was Reprosil-Pur Basic C18 (250×10mm, 5 μm, Beim Brueckle14-D-72119Ammerbuch, Germany), and the mobile phase was 27% water (0.02% diethylamine)-73% ac...

Embodiment 2

[0051] Embodiment 2: the chemical synthesis of sino-wcj-43-M1

[0052] Molecular formula: C 29 h 31 NO 6

[0053] Name: 1-hydroxymethylene-4-cinnamyloxy-7,8-didehydro-3,7-dimethoxy-17-methyl-morphinan-6-one, 1-hydroxymethylene-4-cinnamyloxy-7,8- Didehydro-3,7-dimethoxy-17-methyl-morphinan-6-one.

[0054] Using sinomenine hydrochloride as a raw material, heat and reflux with paraformaldehyde to generate 1-hydroxymethylene sinomenine shown in formula 1; 1-hydroxymethylene sinomenine and tert-butyldimethylchlorosilane, Imidazole and 4-dimethylaminopyridine were reacted to obtain intermediate 2; compound 2 was reacted with cinnamic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethyl The reaction of aminopyridine gives intermediate 3; the reaction of compound 3 with hydrogen fluoride and pyridine gives the target compound sino-wcj-43-M1.

[0055]

[0056] Step 1: Weigh 10.0 g of sinomenine hydrochloride, dissolve it in 200 ml of water, add 20.0...

experiment example 1

[0062] Experimental method: 5 male SD rats in each group, administered orally at 50 mg / kg, fasted for 12 hours before the experiment, and had free access to water. At 10, 30 min, 1, 2, 4, 6, 8, 12, and 24 h after administration, blood was collected continuously from the inner canthus venous plexus, anticoagulated with heparin, centrifuged to separate plasma, acetonitrile precipitated protein, and HPLC was used to determine sino-wcj in plasma -43 and sino-wcj-43-M1 content. The measured experimental data application WinNonlin 6.3 software to calculate the pharmacokinetic parameters.

[0063] Experimental results: After intragastric administration of sino-wcj-43 to rats, the prototype drug was not detected in the plasma within the quantitative range of 100-5000ng / ml, but the metabolite sino-wcj-43-M1 could be detected. At the peak, the average peak plasma concentration is 2626ng / ml, AUC 0-t 10281h*ng / ml ( figure 1 ). The experimental results show that after the drug is admin...

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PUM

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Abstract

The invention belongs to the technical field of medicines, and particularly discloses a sinomenine derivative metabolite sino-wcj-43-M1 as shown in a formula (I), a preparation method thereof, and application thereof in preparation of medicines for preventing or treating aplastic anemia. According to the present invention, the pharmacokinetic research results show that the sino-wcj-43-M1 is the main existence form of the sino-wcj-43 in the body; the method comprises the following steps: hydrolyzing sino-wcj-43 by using esterase, and separating and purifying to obtain the new compound sino-wcj-43-M1, or synthesizing sino-wcj-43-M1 by using sinomenine hydrochloride as a raw material and adopting a chemical synthesis method. The compound has an obvious effect similar to sino-wcj-43 for treating aplastic anemia, and can be applied to clinical treatment of aplastic anemia in the form of a monomer or a medicinal composition.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a metabolite of a sinomenine derivative - a new compound sino-wcj-43-M1 or a pharmaceutically acceptable salt thereof and a preparation method thereof, and a metabolite containing the derivative metabolite or its A pharmaceutical composition of pharmaceutically acceptable salts and its application in the preparation of prevention or treatment of aplastic anemia. Background technique [0002] Aplastic anemia, referred to as aplastic anemia (AA), is a relatively serious blood system disease, which is a bone marrow hematopoietic failure disease caused by physical, chemical, biological or other reasons. Anemia, bleeding, and infection caused by decreased blood cells can be life-threatening in severe cases. Hematopoietic stem cell transplantation is currently the only treatment that can cure aplastic anemia. However, due to the difficulty in matching transplantation and the high ri...

Claims

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Application Information

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IPC IPC(8): C07D221/28A61K31/485A61P7/06
CPCC07D221/28A61P7/06
Inventor 吉腾飞林明宝张梓倩侯琦白金叶马培李旭昱王洪建
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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